S258: IPH6501 IS A FIRST-IN-CLASS TETRASPECIFIC ANTIBODY-BASED NATURAL KILLER CELL ENGAGER THERAPEUTIC DEVELOPED FOR THE TREATMENT OF B-CELL NON-HODGKIN’S LYMPHOMAS
Authors: Olivier Demaria, Guillaume Habif, Francois Le Floch, Marianna Muller, Laura Chiossone, Romain Remark, Marie Vetizou, Nadia Maurel, Ariane Morel, Laurent Gauthier, Yannis Morel, Carine Paturel, Eric Vivier
Journal: HemaSphere (2023)

Background: CD20 is strongly and homogeneously expressed on all mature B-cells and on the majority of mature B-cell neoplasms. Despite several generations of CD20-targeting drugs including rituximab, ofatumumab, and obinutuzumab, and more recent approvals of new CD20-targeting agents, innovative strategies are still needed for B-NHL patients who relapse or are refractory (R/R) after multiple lines of treatment. Recently, clinical responses following CAR-NK cell infusions without major toxic effects were observed in R/R patients with hematologic malignancies, including B-NHL(1), highlighting the therapeutic potential of NK cells in these indications. Aims: We are developing IPH6501, a CD20-targeting tetraspecific antibody-based NK cell engager therapeutic to harness the antitumor functions of NK cells in B-NHL patients. Methods: IPH6501 co-engages the two activating receptors NKp46 and CD16a (FcγRIIIa), and the β-chain (CD122) of the interleukin-2 receptor (IL-2R) expressed on NK cells, as well as the CD20 target antigen on malignant B cells. The IL-2R binding element in IPH6501 is an IL-2 variant (IL-2v) engineered with point mutations to abolish the binding to the IL-2Rα chain (CD25), to reduce the risk of toxicity and interaction with immunosuppressive Tregs. Results: IPH6501 preferentially redirected IL-2v to NK cells by binding with high affinity to NKp46 and CD16a, and promoted their activation and proliferation. CD20-targeting by IPH6501 was required to trigger cytotoxic activity of NK cells against CD20+ target cells, and IPH6501 potently killed tumor cells, even with very low expression levels of CD20. IPH6501 showed better in vitro control of tumor cell growth by NK cells than the CD20-targeting clinical benchmark antibodies rituximab and the Fc-optimized obinutuzumab. Treatment of mice with a surrogate of IPH6501, recognizing mouse NKp46, resulted in high NK cell proliferation and activation. IPH6501 surrogate also showed potent antitumor activity in an aggressive subcutaneous B-NHL xenograft model in immunocompromised mice and in a disseminated mouse tumor model expressing human CD20 injected intravenously into immunocompetent animals. In non-human primates, a well-tolerated dose of IPH6501 resulted in NK cell expansion, with minimal increase in systemic cytokine levels, and to the depletion of CD20+ B cells in circulation and lymphoid tissues. Flow cytometric analysis of samples from R/R B-NHL patients revealed that NK cell numbers in blood were within normal range values, and NKp46 expression was maintained in blood and tumor-involved lymph nodes. Of note, in contrast to NKp46, cell surface expression of CD16 was down-regulated on NK cells in B-NHL patient’s lymph nodes, suggesting a potential therapeutic advantage of targeting NKp46 with IPH6501 in B-NHL compared with classical monoclonal antibodies. IPH6501 stimulated NK cell proliferation and CD20+ cell depletion ex vivo in PBMC samples from R/R B-NHL patients, which compared favourably with a control CD3xCD20 T cell engager. Summary/Conclusion: Our preclinical data showed that IPH6501, a CD20-targeting tetraspecific antibody-based NK cell engager therapeutic, could be a powerful first-in-class new asset to harness the anti-tumor functions of NK cells in CD20+ B-cell malignancies. IPH6501 is expected to enter FIH clinical study in 2023. 1.Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, et al. Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. N Engl J Med. 2020;382(6):545-53. 2.Demaria O, Gauthier L, Vetizou M, Blanchard Alvarez A, Vagne C, Habif G, et al. Antitumor immunity induced by antibody-based natural killer cell engager therapeutics armed with not-alpha IL-2 variant. Cell Rep Med. 2022;3(10):100783. Keywords: B cell lymphoma, NK cell, Immunotherapy, Antibody targeting